Female germline stem cells in ovarian regeneration: a two-layer core signaling network and targeted therapeutic strategies for diminished ovarian reserve

Diminished ovarian reserve (DOR) is a common reproductive disorder marked by progressive depletion. Conventional treatments, including hormone replacement therapy, relieve symptoms but do not restore the depleted follicle pool. This review synthesizes current evidence on female germline stem cells (FGSCs) and their role in ovarian regeneration. We propose a two-layer core signaling network that hierarchically integrates endogenous FGSC fate regulation: an inner PI3K/Akt/mTOR and Wnt/β-catenin-centered hub sustaining stemness and viability, and an outer regulatory layer (RA, YAP/TAZ, BMP, Hedgehog) modulating meiotic initiation and oocyte maturation. Small-molecule compounds, biotechnologies, and traditional Chinese medicine interventions target core nodes of this network. A hypothetical sequential therapeutic strategy, consisting of core hub priming followed by differentiation induction, is proposed as a testable hypothesis that requires preclinical validation. This integrative model offers a theoretical basis for multi-target and staged DOR therapies. It is proposed as an interpretive framework, not a validated signaling map. A conceptual Two-Layer Core Network is proposed to organize the complex regulation of FGSC fate. We posit that differentiation competence is conditionally dependent on prior proliferative stabilization. This hierarchy offers a testable framework for sequencing multi-target therapeutic interventions for DOR. The model distinguishes established evidence from speculative mechanisms to guide future research.